PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the prototypical disease of poverty as it disproportionately affects marginalized and impoverished communities. In the US, TB rates are unacceptably high among homeless persons who have a 10-fold increase in TB incidence as compared to the general population(1). In California, the rate of TB is more than twice the national case rate and recent TB outbreaks have been alarming. An estimated 2.4 million Californians have TB Infection (TBI), which can progress to active TB disease. Among persons with active TB disease, over 10% die during treatment, with mortality being even higher among homeless persons with TB. While TB can be prevented by treating TBI before it develops into infectious, symptomatic disease, individual factors such as high prevalence of psychosocial comorbidities, unstable housing and limited access to care have led to poor adherence and completion of TBI treatment among homeless persons. Given the complex health disparity factors that affect TBI treatment adherence among homeless persons, and in line with the PA-16-161, Exploratory/Development Research Grant Program (R21), we will assess the feasibility of a theoretically-based novel model of care our team has successfully investigated and now plan to extend to the area of TBI among persons with complex chronic illness. In this proposal, we will develop and pilot test an innovative, community-based directly observed intervention, including delivery of the 12-dose therapy (3HP; rifapentine [RPT] plus isoniazid [INH]) weekly. We will address critical individual level factors which are potential mechanisms that underlie health disparities in completing TBI treatment among the predominantly minority homeless. We hypothesize that improving these conditions, and promoting health by focused screening for TBI, and early detection and treatment for these vulnerable adults will improve TB treatment completion and prevent future TB disease. The proposed pilot study builds on the investigators' extensive research on TBI treatment adherence, and reducing risk for poor adherence to TBI treatment. Our innovative theoretically-based health promotion intervention program will be focused on: 1) completion of TBI treatment, 2) reducing substance use; 3) improving mental health; and 4) improving critical social determinants of TB risk (unstable housing and poor health care access) among homeless adults in the highest TB prevalence area in Los Angeles. This new treatment, delivered by a guided Community Health Worker has not been tested among a homeless population previously and provides testing of theoretical approaches which will advance science. In Phase I, we plan to utilize community participatory approaches to develop and refine the culturally-sensitive intervention program and to assess for acceptability and feasibility. In Phase 2, we will assess the impact of the intervention, as a single arm study, among 76 eligible TBI homeless adults on completion of 3HP treatment, decrease in drug and alcohol use, improved access to care, and shelter stability. Completion of 3HP will be compared to the completion rate of 65% conducted by our collaborator in a clinic-based setting among homeless adults. The proposed pilot data will be the first to evaluate an innovative method of promoting the health of at-risk homeless persons who suffer extensive health disparities and will inform an ensuing large multi-site RO1 application.